Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][NH:7][C:8]([C:10]1[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:13]([CH3:16])=[N:14][CH:15]=1)=[O:9].[CH3:32]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[CH2:6][N:7]([CH3:32])[C:8]([C:10]1[C:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:12][C:13]([CH3:16])=[N:14][CH:15]=1)=[O:9]
Reactant: Cc1ncc(C(=O)NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: O
Product: Cc1ncc(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2)n1
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of 0.67 g (1.52 mmol) methyl-4-phenyl-pyrimidine-5-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide in 10 ml N,N-dimethylformamide 0.08 g (1.98 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.15 ml (2.4 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 50 ml H2O, 50 ml brine and 50 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/hexane 4:1) to give 0.50 g (72%) 2-methyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless oil, MS (EI): 453 (M+).
Reaction SMILES: [Zn]([CH2:4][CH3:5])CC.ClCI.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=[CH2:22])[CH:18](O)C1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>ClCCCl>[C:9]([O:13][C:14]([N:16]1[CH2:5][CH2:4][C:19]2([CH2:18][CH2:22]2)[CH2:20][CH2:21]1)=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1O
Reactant: CC[Zn]CC
Agent: ClCI
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56791.1 %

Procedure:
To a solution of Et2Zn (37.5 ml, 1.1M solution in toluene, 0.04 mmol) in DCE (80 ml) at 0° C. was added chloroiodomethane (5.99 ml, 0.08 mmol) under Ar. This mixture was stirred for 15 minutes before a solution of 3-hydroxy-4-methylene-piperidine-1-carboxylic acid tert-butyl ester (J. Org. Chem. 2001, 66, 2487) (4.19 g, 0.02 mmol) in DCE (10 ml) was added, after which time the reaction was stirred for 0.5 h at 0° C. and then allowed to reach room temperature, stirring for a further 1 h. The reaction was then quenched by addition of saturated NH4Cl, separated, and the organic dried (Na2SO4) and concentrated. Purfication by flash column chromatography (EtOAc:n-heptane 2:8-1:1) afforded the title product (2.4 g, 54%) as a crystalline solid. MS: 228.2 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:39][CH:38]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(CC(C)C)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-methoxy-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.79-0.90 (m, 6H), 1.46 (ddd, J=13.33, 6.85, 6.72 Hz, 1H), 1.64 (ddd, J=13.63, 7.09, 6.91 Hz, 1H), 1.87-1.98 (m, 1H), 3.67-3.77 (m, 4H), 6.87-6.95 (m, 2H), 7.43-7.54 (m, 4H), 7.59-7.69 (m, 3H), 7.73 (d, J=8.07 Hz, 2H); Calcd for C26H25F3O3 (M+Na) 465.18, Found 465.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C.O>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cccc2)cc1

Procedure:
To a stirred solution of methyl 4-aminobenzoate (7.6 g) in acetic acid (25 ml) was added 2,5-dimethoxytetrahydrofuran (6.6 g) dropwise and the reaction mixture was heated under reflux for 1 hour and then diluted with water. The resulting precipitated crystals were purified by column chromatography on silica gel. Recrystallization from ethyl acetate-hexane afforded the title compound as colorless plates (7.5 g, 74%), m.p. 128°-129° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[C:14]([CH3:29])([CH3:28])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:29][C:14]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:16])([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH3:28]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(Br)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
In 75 ml of dry N,N-dimethylformamide are dissolved 14.7 g of N-hydroxyphthalimide and 27.2 g of p-nitrobenzyl α-bromoisobutyrate, followed by addition of 12.4 g of potassium carbonate. The mixture is stirred at room temperature for one hour. The stirring becomes difficult due to precipitation of an orange-colored solid and, therefore, 75 ml of dry N,N-dimethylformamide is added. After 24 hours of stirring at room temperature, the reaction mixture is concentrated under reduced pressure to about half its original volume and the concentrate is put in 700 ml of water with ice-cooling and stirring. The mixture is further stirred for 30 minutes and the resultant crystalline precipitate is recovered by filtration and washed with water. The crystals are dissolved in 500 ml of methylene chloride, washed with water and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure. The solid residue is washed with ether-petroleum ether (1:1) and a small amount of ether in this order to give 27.0 g of N-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxy]phthalimide as colorless crystals, m.p. 145°-146° C.
Reaction SMILES: [NH:1]([C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:24])[C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[OH:11])=[O:5])[CH3:3].O[N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl>[NH:1]([C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:24])[C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:11])[O:12][N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47])=[O:5])[CH3:3]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)O)C(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 7846.1 %

Procedure:
To a solution of palmitoyl-L-Ala-D-Glu(OH)OBzl (1)(1.84 g) in a mixture of tetrahydrofuran (20 ml) and chloroform (30 ml) were added N-hydroxysuccinimide (425 mg) and dicyclohexylcarbodiimide (728 mg). The reaction mixture was kept for 18 hours at room temperature and the precipitate was filtered off and washed with chloroform. The filtrate was concentrated in vacuo and the diisopropylether was added to the residue. The product was collected and dried to afford palmitoyl-L-Ala-D-Glu(OSu)OBzl (2)(170 g).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)[CH3:3].[NH2:26][C:27]1[N:32]=[C:31](Cl)[C:30]([C:34]#[N:35])=[C:29]([CH3:36])[N:28]=1.C(N(CC)CC)C>CS(C)=O>[NH2:26][C:27]1[N:32]=[C:31]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15]2)[CH3:3])[C:30]([C:34]#[N:35])=[C:29]([CH3:36])[N:28]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1C1CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c1C#N
Temperature: 85 °C

Procedure:
To a 25 mL pear flask were added the mixture of diastereomers of tert-butyl 3-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidine-1-carboxylate (0.057 g, 0.17 mmol) and 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.042 g, 0.25 mmol) in DMSO (1 mL). Triethylamine (0.069 mL, 0.50 mmol) was added and the mixture was heated to 85° C. for 14 hours. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by liquid chromatography (SiO2, 25-100% EtOAc/hexanes). The product-containing fractions from two different peaks were pooled separately and concentrated in vacuo to give the title diastereomers. Peak 1 (shorter retention time, 19 mg, 24%): 1H NMR (400 MHz, CDCl3) δ ppm 0.69-0.85 (m, 5H), 1.32-1.51 (m, 22H), 2.15-2.40 (m, 8H), 3.33-3.49 (m, 2H), 3.52-3.86 (m, 8H), 4.70 (dd, J=10.74, 7.45 Hz, 1H), 5.27 (br s, 1H), 5.62-5.75 (m, 1H), 5.82-5.96 (m, 2H), 6.60 (br s, 2H), 6.73 (d, J=8.84 Hz, 1H), 7.19 (s, 2H), 7.33-7.45 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C25H32N8O2, 477. found 477. Peak 2 (longer retention time, 41 mg, 52%): 1H NMR (400 MHz, CDCl3) δ ppm 0.66-0.90 (m, 3H), 1.39-1.52 (m, 15H), 1.88-2.07 (m, 3H), 2.21-2.40 (m, 5H), 3.30-3.89 (m, 10H), 5.02-5.20 (m, 2H), 5.65 (t, J=6.44 Hz, 1H), 6.61 (d, J=3.03 Hz, 1H), 7.14-7.24 (m, 2H), 7.28-7.46 (m, 2H); ESI-MS m/z [M+H]+ calc'd for C25H32N8O2, 477. found 477.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH2:16](O)[CH3:17]>>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A steady stream of anhydrous hydrochloric acid was bubbled subsurface into a solution of 2-naphthylacetic acid (251.38 grams, 1.35 mol) dissolved in ethanol (1760 mL) over a period of 10 minutes. The resulting solution was stirred at ambient temperature until complete as determined by hplc (2 hours). The reaction mixture was concentrated to dryness. The resulting oil was dissolved in ethyl acetate (200 mL) and filtered through silica gel (300 grams) eluting the product with ethyl acetate (1400 mL). The filtrate was concentrated to give 286.33 grams (99%) of ethyl 2-(2-naphthyl)acetate as a colorless oil. MS (FIA) m/z 215.3 [(M+H)+]. 1H nmr (DMSO-d6): δ1.15-1.24 (t, 3H), 3.81-3.86 (d, 2H), 4.07-4.15 (q, 2H), 7.41-7.55 (m, 3H), 7.80-7.92 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]3)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[Li]CCCC.[O:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1.[Cl-].[NH4+]>O1CCCC1>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([C:34]4([OH:37])[CH2:35][CH2:36][O:31][CH2:32][CH2:33]4)=[CH:7][CH:6]=3)[N:9]=2)[CH2:19][CH2:20]1)[CH3:25]
Reactant: CCN1CCN(c2nc(-c3ccc(Br)cc3)cc3ccccc23)CC1
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(-c3ccc(C4(O)CCOCC4)cc3)cc3ccccc23)CC1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A solution of the resulting 3-(4-bromophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline (0.61 g) in tetrahydrofuran (30 ml) was cooled to −78° C., followed by the dropwise addition of 1.6M n-BuLi (1.1 ml) in nitrogen atmosphere. Fifteen minutes later, a solution of tetrahydropyran-4-one (0.17 g) in tetrahydrofuran (1 ml) was added thereto, and the temperature of the reaction mixture was gradually raised to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound as a pale yellow oil (0.21 g, yield; 32.1%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][CH:6]=1)=[O:4].[P:13]([O:18]C)([O:16][CH3:17])[O:14][CH3:15]>>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][P:13]([O:16][CH3:17])([O:14][CH3:15])=[O:18])=[CH:7][CH:6]=1
Reactant: COP(OC)OC
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(CP(=O)(OC)OC)cc1

Procedure:
Methyl 4-(bromomethyl) benzoate (compound 47) (11.2 g, 49 mmol) was dissolved in 25 mL trimethyl phosphite and refluxed under N2 for 5 hrs. Excess trimethyl phosphite was removed by co-distillation with toluene to give crude 4-(Dimethoxy-phosphorylmethyl)-benzoic acid methyl ester (compound 48).
Reaction SMILES: C1(=O)[N:5]([O:6][CH2:7][C:8]([O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])C(=O)C2=CC=CC=C12.O.NN>C(Cl)Cl.CO>[NH2:5][O:6][CH2:7][C:8]([O:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: O=C(CON1C(=O)c2ccccc2C1=O)OC(c1ccccc1)c1ccccc1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: NOCC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a solution of benzhydryl 2-phthalimidooxyacetate (10 g) in methylene chloride (100 ml) was added a solution of hydrazine hydrate (6.08 g) in methanol (7 ml). The reaction mixture was stirred at ambient temperature for an hour. The precipitates were collected by filtration and washed with methylene chloride. The filtrate and the washings were combined, adjusted to pH 7.0 with conc. hydrochloric acid, and washed with a saturated aqueous sodium chloride, and then dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 2-aminooxyacetate (6.0 g).
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:21][O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([CH3:15])([C:17](=[O:19])[NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=2)[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCc2cccc(C(F)(F)F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 3-trifluoromethyl-benzylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H24F3NO5 [M−H]−: 438.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (31.2 g, 200 mmole) in dry THF (250 ml) was added to a solution of 4-fluorophenylmagnesium bromide in dry THF at -60° C. The mixture was allowed to warm to 25° C. and quenched with saturated NH4Cl solution and extracted with ether. The extracts were dried with Na2SO4 and the solvent removed in vacuo. The residue was crystallized from hexane to give the product (89%, mp: 133°-135° C.). Calc'd for C14H17FO3 : C, 66.66%; H, 6.80%. Found: C, 66.54%; H, 7.12%.
Reaction SMILES: [C:1]([C@@H:4]([C@H:8]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9]1)[CH2:5][CH:6]=[CH2:7])([OH:3])=O.ON1C2N=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C.Cl.[NH2:39][C@@H:40]([C:52]([CH3:55])([CH3:54])[CH3:53])[C:41]([NH:43][C@@H:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH3:45])=[O:42].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:14][C:10]1([CH3:15])[O:9][C@@H:8]([C@@H:4]([CH2:5][CH:6]=[CH2:7])[C:1]([NH:39][C@H:40]([C:41]([NH:43][C@@H:44]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH3:45])=[O:42])[C:52]([CH3:53])([CH3:54])[CH3:55])=[O:3])[C:12](=[O:13])[O:11]1
Reactant: C[C@@H](NC(=O)[C@@H](N)C(C)(C)C)c1ccccc1
Reactant: C=CC[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)[C@@H]1OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A portion of the crude (4S)-4-[(1R)-1-carboxy-but-3-enyl]-2,2-dimethyl-1,3-dioxolan-5-one from b) above (calculated from the NMR to contain 1.54 g, 7.19 mmol) and 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (1.09 g, 7.55 mmol) in anhydrous dichloromethane (30 mL) were mixed and cooled to 0° C. under nitrogen. N-(Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.60 g, 8.27 mmol) was added, and the mixture was stirred for 1.5 h at 0° C. (2S)-Amino-3,3-dimethyl-N-[(1R)-1-phenylethyl]butanamide hydrochloride (Preparation 1)(2.15 g, 7.55 mmol) was added, followed by diisopropylethylamine (1.37 mL, 7.55 mmol). After another 45 min, the mixture was allowed to warm to room temperature. After 3 h at room temperature, the mixture was partitioned between ethyl acetate (200 mL) and pH 7 aqueous phosphate buffer (100 mL). The organic layer was washed with sodium bicarbonate, brine, dried (Na2SO4), and concentrated under reduced pressure. The resulting foam crystallised upon addition of ether, and the white solid (1.89 g) was filtered off. Recystallisation from ethyl acetate/hexane gave (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-N-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]pent-4-enamide as a white solid (1.30 g, 42%, as a single diastereomer).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[NH:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C([N+]([O-])=O)=CC=C([Cl-:25][C:26]([O-])=[O:27])C=1.[C:29]([C:31]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]1)#[N:30].C(N(CC)CC)C>O1CCCC1.ClCCl>[ClH:25].[C:29]([C:31]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:32][CH2:33][N:34]([CH2:37][CH2:38][CH2:39][NH:40][C:26]([N:14]2[CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:10][CH2:11][CH2:12][C:13]2=[O:15])=[O:27])[CH2:35][CH2:36]1)#[N:30]
Reactant: N#CC1(c2ccccc2)CCN(CCCN)CC1
Reactant: O=C1CCCC(c2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Product: N#CC1(c2ccccc2)CCN(CCCNC(=O)N2C(=O)CCCC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride in mineral oil (60%, 65 mg, 1.63 mmol) was suspended in 3 mL of tetrahydrofuran. To this suspension was added 3 mL of a solution of 6-phenylpiperidin-2-one (235 mg, 1.34 mmol) and the mixture was stirred at ambient temperature for 30 minutes. The resulting solution was transferred via syringe to solution of 4-nitrophenylchloroformate (269 mg, 1.33 mmol) in tetrahydrofuran (4 mL) which had already been chilled to −78° C. The reaction mixture was stirred at −78° C. for 2 hours and then at ambient temperature for 30 minutes. The reaction mixture was then evaporated to dryness. One third of the resulting residue (150 mg, 0.441 mmol) was dissolved in 5 mL of dichloromethane. 4-cyano-4-phenylpiperidine propylamine (113 mg, 0.464 mmol) and triethylamine (139 mL, 0.997 mmol) were added to this solution, and the resulting yellow mixture was stirred at ambient temperature for 18 hours, and then evaporated to dryness. The resulting residue was purified by “flash” chromatography (97:3:0.3 dichloromethane:methanol:ammonium hydroxide). The product fractions were evaporated to give a yellow oil. The residue was purified by “flash” chromatography (1:1 ethyl acetate:hexanes). The product fractions were evaporated to dryness. The residue was then treated with HCl-saturated ethyl acetate, evaporated to dryness, and reconcentrated from diethyl ether twice to give the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:16]=[C:9]2[N:10]=[CH:11][C:12]([Br:15])=[C:13]([CH3:14])[C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[Br:15][C:12]1[CH:11]=[N:10][C:9]2=[N:16][N:6]([CH2:5][C:2]([NH:1][C:24](=[S:25])[C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=3)([C:3]#[N:4])[CH3:17])[N:7]=[C:8]2[C:13]=1[CH3:14]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: Cc1c(Br)cnc2nn(CC(C)(N)C#N)nc12
Product: Cc1c(Br)cnc2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, 2-amino-3-(6-bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-2-methylpropionitrile (90 mg, described in Example 153) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (65 mg, 43%). Rf=0.4 (1:1 EA/heptane). MS (ES): M/Z [M−H]=497. 1H NMR: (400 MHz, DMSO-d6): 1.76 (s, 3H), 2.56 (s, 3H), 5.40 (d, 1H), 5.54 (d, 1H), 7.82-7.94 (m, 4H), 8.86 (s, 1H) and 8.93 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).